The present invention relates to methods for treating pain. In particular, the present invention relates to methods for treating pain by intraspinal administration of a neurotoxin.
Many, if not most ailments of the body cause pain. Generally pain is experienced when the free nerve endings which constitute the pain receptors in the skin as well as in certain internal tissues are subjected to mechanical, thermal or chemical stimuli. The pain receptors transmit signals along afferent neurons into the central nervous system and thence to the brain.
The causes of pain can include inflammation, injury, disease, muscle spasm and the onset of a neuropathic event or syndrome. Ineffectively treated pain can be devastating to the person experiencing it by limiting function, reducing mobility, complicating sleep, and dramatically interfering with the quality of life.
Inflammatory pain can occur when tissue is damaged, as can result from surgery or due to an adverse physical, chemical or thermal event or to infection by a biologic agent. Although inflammatory pain is generally reversible and subsides when the injured tissue has been repaired or the pain inducing stimulus removed, present methods for treating inflammatory pain have many drawbacks and deficiencies. Thus, the typical oral, parenteral or topical administration of an analgesic drug to treat the symptoms of pain or of, for example, an antibiotic to treat inflammatory pain causation factors can result in widespread systemic distribution of the drug and undesirable side effects. Additionally, current therapy for inflammatory pain suffers-from short drug efficacy durations which necessitate frequent drug readministration with possible resulting drug resistance, antibody development and/or drug dependence and addiction, all of which are unsatisfactory. Furthermore, frequent drug administration increases the expense of the regimen to the patient and can require the patient to remember to adhere to a dosing schedule.,
Neuropathic pain is a persistent or chronic pain syndrome that can result from damage to the nervous system, the peripheral nerves, the dorsal root ganglion or dorsal root, or to the central nervous system. Neuropathic pain syndromes include allodynia, various neuralgias such as post herpetic neuralgia and trigeminal neuralgia, phantom pain, and complex regional pain syndromes, such as reflex sympathetic dystrophy and causalgia. Causalgia is characterized by spontaneous burning pain combined with hyperalgesia and allodynia.
Unfortunately, current methods to treat neuropathic pain, such as by local anesthetic blocks targeted to trigger points, peripheral nerves, plexi, dorsal roots, and to the sympathetic nervous system have only short-lived antinociceptive effects. Additionally, longer lasting analgesic treatment methods, such as blocks by phenol injection or cryotherapy raise a considerable risk of irreversible functional impairment. Furthermore, chronic epidural or intrathecal (collectively xe2x80x9cintraspinalxe2x80x9d) administration of drugs such as clonidine, steroids, opioids or midazolam have significant side effects and questionable efficacy.
Tragically there is no existing method for adequately, predictably and specifically treating established neuropathic pain (Woolf C. et al., Neuropathic Pain: Aetiology, Symptoms, Mechanisms, and Management, Lancet 1999;353:1959-64) as present treatment methods for neuropathic pain consists of merely trying to help the patient cope through psychological or occupational therapy, rather than by reducing or eliminating the pain experienced.
Spasticity or muscle spasm can be a serious complication of trauma to the spinal cord or other disorders that create damage within the spinal cord and the muscle spasm is often accompanied by pain. The pain experienced during a muscle spasm can result from the direct effect of the muscle spasm stimulating mechanosensitive pain receptors or from the indirect effect of the spasm compressing blood vessels and causing ischemia. Since the spasm increases the rate of metabolism in the affected muscle tissue, the relative ischemia becomes greater creating thereby conditions for the release of pain inducing substances.
Within the enclosure by the vertebral: canal for the spinal cord by the bones of the vertebrae, the spinal cord is surrounded by three meningeal sheaths which are continuous with those which encapsulate the brain. The outermost of these three meningeal sheaths is the dura matter, a dense, fibrous membrane which anteriorally is separated from the periosteum of the vertebral by the epidural space. Posterior to the dura matter is the subdural space. The subdural space surrounds the second of the three meningeal sheaths which surround the spinal cord, the arachnoid membrane. The arachnoid membrane is separated from the third meningeal sheath, the pia mater, by the subarachnoid or intrathecal space. The subarachnoid space is filled with cerebrospinal fluid (CSF). Underlying the pia mater is the spinal cord. Thus the progression proceeding inwards or in posterior manner from the vertebra is the epidural space, dura mater, subdural space, arachnoid membrane, intrathecal space, pia matter and spinal cord.
Therapeutic administration of certain drugs intraspinally, that is to either the epidural space or to the intrathecal space, is known. Administration of a drug directly to the intrathecal space can be by either spinal tap injection or by catheterization. Intrathecal drug administration can avoid the inactivation of some drugs when taken orally as well and the systemic effects of oral or intravenous administration. Additionally, intrathecal administration permits use of an effective dose which is only a fraction of the effective dose required by oral or parenteral administration. Furthermore, the intrathecal space is generally wide enough to accommodate a small catheter, thereby enabling chronic drug delivery systems. Thus, it is known to treat spasticity by intrathecal administration of baclofen. Additionally, it is known to combine intrathecal administration of baclofen with intramuscular injections of botulinum toxin for the adjunct effect of intramuscular botulinum for reduced muscle spasticity. Furthermore, it is known to treat pain by intraspinal administration of the opioids morphine and fentanyl, as set forth in Gianno, J., et al., Intrathecal Drug Therapy for Spasticity and Pain, Springer-Verlag (1996), the contents of which publication are incorporated herein by reference in its entirety.
The current method for intrathecal treatment of chronic pain is by use of an intrathecal pump, such as the SynchroMed(copyright) Infusion System, a programmable, implanted pump available from Medtronic, Inc., of Minneapolis, Minn. A pump is required because the antinociceptive or antispasmodic drugs in current use have a short duration of activity and must therefore be frequently readministered, which readministration is not practically carried out by daily spinal tap injections. The pump is surgically placed under the skin of the patient""s abdomen. One end of a catheter is connected to the pump, and the other end of the catheter is threaded into a CSF filled subarachnoid or intrathecal space in the patient""s spinal cord. The implanted pump can be programmed for continuous or intermittent infusion of the drug through the intrathecally located catheter. Complications can arise due the required surgical implantation procedure and the known intrathecally administered drugs for pain have the disadvantages of short duration of activity, lipid solubility which permits passage out of the intrathecal space and systemic transport and/or diffusion to higher CNS areas with potential respiratory depression resulting.
Thus, a significant problem with many if not all of the known intrathecally administered drugs used to treat pain, whether administered by spinal tap or by catheterization, is that due to the drug""s solubility characteristics, the drug can leave the intrathecal space and additionally due to poor neuronal binding characteristics, the drug can circulate within the CSF to cranial areas of the CNS where brain functions can potentially be affected.
The anaerobic, gram positive bacterium Clostridium botulinum produces a potent polypeptide neurotoxin, botulinum toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. The spores of Clostridium botulinum are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a Clostridium botulinum culture or spores. The botulinum toxin can apparently pass unattenuated through the lining of the gut and attack the central nervous system. The highest cranial nerves are affected first, followed by the lower cranial nerves and then the peripheral motor neurons. Symptoms of untreated botulinum toxin poisoning can progress from and include medial rectus paresis, ptosis, sluggish pupillary response to light, difficulty walking, swallowing, and speaking, paralysis of the respiratory muscles and death.
Botulinum toxin type A is the most lethal natural biological agent known to man. It has been determined that 39 units per kilogram (U/kg) of intramuscular BOTOX(copyright)1 is a LD50 in primates. One unit (U) of botulinum toxin can be defined as the LD50 upon intraperitoneal injection into mice. BOTOX(copyright) contains about 4.8 ng of botulinum toxin type A complex per 100 unit vial. Thus, for a 70 kg human a LD50 of about 40 U/kg would be about 134 ng or 28 vials (2800 units) of intramuscular BOTOX(copyright). Seven immunologically distinct botulinum neurotoxins have been characterized, being respectively neurotoxin serotypes A, B, C1, D, E, F and G each of which is distinguished by neutralization with type-specific antibodies. The neurotoxin component is noncovalently bound to nontoxic proteins to form high molecular weight complexes. The different serotypes of botulinum toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that botulinum toxin type A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is botulinum toxin type B. Additionally, botulinum toxin type B has been determined to be non-toxic in primates at a dose of 480 U/kg which is about 12 times-the primate LD50 for botulinum toxin type A (Moyer E et al., Botulinum Toxin Type B: Experimental and Clinical Experience, being chapter 6, pages 71-85 of xe2x80x9cTherapy With Botulinum Toxinxe2x80x9d, edited by Jankovic, J. et al. (1994), Marcel Dekker, Inc.)
1botulinum toxin type A purified neurotoxin complex, available from Allergan, Inc., of Irvine, Calif. A botulinum toxin type A complex is also available from Porton Products, Ltd., U.K. under the trade name DYSPORT) 
Minute quantities of botulinum toxin have been used to reduce excess skeletal and smooth muscle and sphincter contraction. The botulinum toxin can be injected directly into the hyperactive or hypertonic muscle or its immediate vicinity and is believed to exert its effect by entering peripheral, presynaptic nerve terminals at the neuromuscular junction and blocking the release of acetylcholine. The affected nerve terminals are thereby inhibited from stimulating muscle contraction, resulting in a reduction of muscle tone. Thus, when injected intramuscularly at therapeutic doses, botulinum toxin type A can be used to produce a localized chemical denervation and hence a localized weakening or paralysis and relief from excessive involuntary muscle contractions.
Clinical effects of peripheral intramuscular botulinum toxin type A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of botulinum toxin type A averages about three months. Muscles therapeutically treated with a botulinum toxin eventually recover from the temporary paralysis induced by the toxin, due possibly to the development of new nerve sprouts or to reoccurrence of neurotransmission from the original synapse, or both. A nerve sprout may establish a new neuromuscular junction. Thus, neuromuscular transmission can gradually return to normal over a period of several months.
In skeletal and smooth muscle tissues botulinum toxin appears to have no appreciable affinity for organs or tissues other than cholinergic neurons at the neuromuscular junction where the toxin binds to and is internalized by neuronal receptors and, as indicated, block presynaptic release of the neurotransmitter acetylcholine, without causing neuronal cell death.
Botulinum toxins have been used for the treatment of an increasing array of disorders, relating to cholinergic nervous system transmission, characterized, for example, by hyperactive neuromuscular activity in specific focal or segmental striated or smooth muscle regions. Thus, intramuscular injection of one or more of the botulinum toxin serotypes has been used to treat, blepharospasm, spasmodic torticollis, hemifacial spasm, spasmodic dysphonia, oral mandibular dystonia and limb dystonias, myofacial pain, bruxism, achalasia, trembling chin, spasticity, juvenile cerebral palsy, hyperhydrosis, excess salivation, non-dystonic tremors, brow furrows, focal dystonias, tension headache, migraine headache and lower back pain. Not infrequently, a significant amount of pain relief has also been experienced by such intramuscular therapy. These benefits have been observed after local intramuscular injection of, most commonly botulinum toxin type A, or one or another of the other botulinum neurotoxin serotypes. Botulinum toxin serotypes B, C1, D, E and F apparently have a lower potency and/or a shorter duration of activity as compared to botulinum toxin type A at a similar dosage level.
Although all botulinum toxins serotypes apparently inhibit release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory proteins and/or cleaving these proteins at different sites. For example, botulinum types A and E both cleave the 25 kiloDalton (kD) synaptosomal associated protein (SNAP-25), but they target different amino acid sequences within this protein. Botulinum toxin types B, D, F and G act on vesicle-associated protein (VAMP, also called synaptobrevin), with each serotype cleaving the protein at a different site. Finally, botulinum toxin type C1 has been shown to cleave both syntaxin and SNAP-25. These differences in mechanism of action may affect the relative potency and/or duration of action of the various botulinum toxin serotypes.
The molecular weight of a secreted botulinum toxin protein molecule, for all seven of the known botulinum toxin serotypes, is about 150 kD. Interestingly, the botulinum toxins are released by Clostridial bacterium as complexes comprising the 150 kD botulinum toxin protein molecule along with associated non-toxin proteins. Thus, the botulinum toxin type A complex can be produced by Clostridial bacterium as 900 kD, 500 kD and 300 kD forms. Botulinum toxin types B and C1 is apparently produced as only a 500 kD complex. Botulinum toxin type D is produced as both 300 kD and 500 kD complexes. Finally, botulinum toxin types E and F are produced as only approximately 300 kD complexes. The complexes (i.e. molecular weight greater than about 150 kD) are believed to contain a non-toxin hemaglutinin protein and a non-toxin and non-toxic nonhemaglutinin protein. These two non-toxin proteins (which along with the botulinum toxin molecule comprise the relevant neurotoxin complex) may act to provide stability against denaturation to the botulinum toxin molecule and protection against digestive acids when toxin is ingested. Additionally, it is possible that the larger (greater than about 150 kD molecular weight) botulinum toxin complexes may result in a slower rate of diffusion of the botulinum toxin away from a site of intramuscular injection of a botulinum toxin complex.
The biochemical mechanism of the effects of botulinum toxin upon central nervous tissues is controversial. Additionally, the number of CNS neurotransmitters affected as well as the extent and nature of the effect of botulinum toxin upon the synthesis, release, accumulation and metabolism of different CNS neurotransmitters is still being determined. In vitro studies have indicated that botulinum toxin inhibits potassium cation induced release of both acetylcholine and norepinephrine from primary cell cultures of brain tissue. Additionally, it has been reported that botulinum toxin inhibits the evoked release of both glycine and glutamate in primary cultures of spinal cord neurons and that in brain synaptosome preparations botulinum toxin inhibits the release of each of the neurotransmitters acetylcholine, dopamine, norepinephrine, CGRP and glutamate.
Botulinum toxin type A can be obtained by establishing and growing cultures of Clostridium botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known procedures. All the botulinum toxin serotypes are initially synthesized as inactive single chain proteins which must be cleaved or nicked by proteases to become neuroactive. The bacterial strains that make botulinum toxin serotypes A and G possess endogenous proteases and serotypes A and G can therefore be recovered from bacterial cultures in predominantly their active form. In contrast, botulinum toxin serotypes C1, D and E are synthesized by nonproteolytic strains and are therefore typically unactivated when recovered from culture. Serotypes B and F are produced by both proteolytic and nonproteolytic strains and therefore can be recovered in either the active or inactive form. However, even the proteolytic strains that produce, for example, the botulinum toxin type B serotype only cleave a portion of the toxin produced. The exact proportion of nicked to unnicked molecules depends on the length of incubation and the temperature of the culture. Therefore, a certain percentage of any preparation of, for example, the botulinum toxin type B toxin is likely to be inactive, possibly accounting for the known significantly lower potency of botulinum toxin type B as compared to botulinum toxin type A. The presence of inactive botulinum toxin molecules in a clinical preparation will contribute to the overall protein load of the preparation, which has been linked to increased antigenicity, without contributing to its clinical efficacy. Additionally, it is known that botulinum toxin type B has, upon intramuscular injection, a shorter duration of activity and is also less potent than botulinum toxin type A at the same dose level.
What is needed therefore is a method for effectively treating pain and/or spasm by intraspinal administration of a pharmaceutical which has the characteristics of long duration of activity, low rates of diffusion out of an intrathecal space where administered, low rates of diffusion to other intrathecal areas outside of the site of administration, specificity for the treatment of pain and limited or insignificant side effects at therapeutic dose levels.
The present invention meets this need and provides methods for effectively treating pain by intraspinal administration of a neurotoxin which has the characteristics of long duration of activity, low rates of diffusion out of an, for example, intrathecal space where administered, low rates of diffusion to other intrathecal areas outside of the site of administration, specificity for the treatment of pain and limited or insignificant side effects at therapeutic dose levels.
A method for treating pain according to the present invention can have the step of intraspinal administration of a neurotoxin to a mammal, thereby alleviating pain experienced by the mammal. Preferably, the neurotoxin used is a botulinum toxin, such as one of, or a combination of one or more, of the botulinum toxin serotypes A, B, C, D, E, F and G. Most preferably, the botulinum toxin used is botulinum toxin type A because of the high potency, ready availability and long history of clinical use of botulinum toxin type A to treat various disorders.
The neurotoxin intraspinally administered according to the methods of the present invention has not been conjugated, attached, adhered to or fused to and is not administered in conjunction with a neuronal targeting moiety. A neuronal targeting moiety is a compound which functionally interacts with a binding site on a neuron causing a physical association between the targeting moiety and/or a conjugate attached to the targeting moiety and the surface of the neuron, such as a primary sensory afferent. Thus, the targeting moiety provides specificity for or binding affinity for one or more type of neurons. In the present invention, any pharmaceutical preparation (i.e. a reconstituted solution of neurotoxin, sodium chloride (saline) and a stabilizer such as albumin) which incorporates a neurotoxin for use according to the disclosed methods is devoid of or essentially free of any deliberately attached or prepared neuronal targeting moiety.
Use of one or more targeting moiety artifacts or constructs is excluded from the scope of the present invention as unnecessary because we have surprisingly discovered that intraspinal neurotoxin administration according to the present invention provides significant pain alleviation even though the neurotoxin is not administrated in conjunction with any non-native or non-inherent to the neurotoxin neuronal targeting moiety. Thus, we unexpectedly discovered that a native neurotoxin, such as botulinum toxin type A, can upon intraspinal administration interact with neurons of the CNS and provide alleviation of pain even though the neurotoxin has not been artificially or manipulatively accorded any neuronal specificity or binding affinity, such as by attachment of a neuronal targeting moiety to the neurotoxin. Prior to our invention, it has been believed, as discussed infra, that a neurotoxin, such as botulinum toxin type A, would upon intraspinal, including intrathecal, administration, exert widespread, unfocused, diffuse and deleterious effects upon the CNS, such deleterious effects including spasticity. Hence, the assumed necessity for a neuronal targeting moiety deliberately attached to the neurotoxin to attenuate or eliminate these presumed detrimental effects resulting from intraspinal administration of a neurotoxin, such a botulinum toxin type A.
We have surprising found that a botulinum toxin, such as botulinum toxin type A, can be intraspinally administered in amounts between about 10xe2x88x923 U/kg and about 60 U/kg to alleviate pain experienced by a mammal, such as a human patient. Preferably, the botulinum toxin used is intraspinally administered in an amount of between about 10xe2x88x922 U/kg and about 50 U/kg. More preferably, the botulinum toxin is administered in an amount of between about 10xe2x88x921 U/kg and about 40 U/kg. Most preferably, the botulinum toxin is administered in an amount of between about 1 U/kg and about 30 U/kg. In a particularly preferred embodiment of the present disclosed methods, the botulinum toxin is administered in an amount of between about 1 U/kg and about 20 U/kg and in some clinical settings the botulinum toxin can advantageously be administered in an amount of between about 1 U/kg and about 10 U/kg. Significantly, the pain alleviating effect of the present disclosed methods can persist for up to 10 days or for up to 20 days and depending upon factors, such as the dosage used, for up to 3 months per neurotoxin administration.
The intraspinal administration of the neurotoxin is preferably by intrathecal administration, such as intrathecally to a cranial, cervical, thoracic, lumbar, sacral or coccygeal region of the central nervous system and the administration step can include the steps of accessing a subarachnoid space of the central nervous system of the mammal, and injecting the neurotoxin into the subarachnoid space. The accessing step can be carried out by effecting a spinal tap.
Alternately, the intraspinal administration step can include the steps of catheterization of a subarachnoid space of the central nervous system of the mammal, followed by injection of the neurotoxin through a catheter inserted by the catheterization step into the subarachnoid space. Note that prior to the injecting step there can be the step of attaching to or implanting in the mammal an administration means for administering the neurotoxin to the central nervous system of the mammal. The administration means can be made up of a reservoir of the neurotoxin, where the reservoir is operably connected to a pump means for pumping an aliquot of the neurotoxin out of the reservoir and into an end of the catheter in the subarachnoid space.
It is important to note that the administration step can be carried out prior to the onset of or subsequent to the occurrence of a nociceptive (inflammatory, neuropathic, injury induced, resulting form a cancer, spasm, etc) event or syndrome experienced by the mammal. Thus, the administration step can be carried out between about more than 0.5 hour before to about 14 days before the onset of the nociceptive event. More preferably, administration step is carried out between about more than 0.5 hour before to about 10 days before the onset of the nociceptive event. Most preferably, the administration step is carried out between about more than 0.5 hour before to about 7 days, 4 days, 24 hours or 6 hours before the onset of the nociceptive event. In a particularly preferred embodiment of the present invention, the administration step is carried out between about 2 hours before to about 5 hours before the onset of the nociceptive event. The present methods can be used to treat the pain associated with allodynia.
A detailed embodiment of a method within the scope of the present invention can include the steps of firstly catheterization of a subarachnoid space of the central nervous system of the mammal by making an incision though the dermis of the mammal, and then threading a catheter through the incision into the subarachnoid space, the catheter having an open first end and a remote open second end. Secondly, attaching to or implanting in the mammal an administration means for administering a botulinum toxin to the subarachnoid space of the central nervous system of the mammal, the administration means comprising a reservoir for holding a multidose amount of the botulinum toxin, the reservoir being connected to a pump means for pumping an aliquot of the botulinum toxin out of the reservoir and into the first end of a catheter, the first end of the catheter being connected to the pump means. Thirdly, activating the pump means, and finally, injecting into the subarachnoid space of the central nervous system of the mammal and through the second end of the catheter between about 10xe2x88x923 U/kg and about 60 U/kg of the botulinum toxin, thereby alleviating pain experienced by the mammal.
Another preferred method within the scope of the present invention is a method for the in vivo attenuation of a nociceptive activity or experience of a human patient, the method comprising the step of intraspinal administration to a human patient a therapeutically effective amount of a botulinum toxin, thereby causing an in vivo attenuation of a nociceptive activity or experience of the human patient. The intraspinal administration step can be carried out subsequent to or prior to the occurrence or onset of a nociceptive activity, experience, sensation or syndrome.
A further preferred method within the scope of the present invention is a method for treating pain by selecting a neurotoxin with antinociceptive activity, choosing a portion of a central nervous system of a patient which influences a nociceptive activity; and intraspinally administering to the portion of the central nervous system chosen the neurotoxin selected.
Notably, the neurotoxin used to practice the present methods can be made by a Clostridial bacterium, such as one or more of the Clostridium botulinum, Clostridium butyricum, and Clostridium beratti species.
Another preferred method within the scope of the present invention is a method for treating pain, the method comprising the step of administering a neurotoxin to the central nervous system or to a dorsal root ganglion of a mammal, thereby alleviating pain experienced by the mammal. A further preferred method within the scope of the present invention is a method for improving patient function, the method comprising the step of administering a neurotoxin to the central nervous system or to dorsal root ganglion of a mammal, thereby improving patient function as determined by improvement in one or more of the factors of reduced pain, reduced time spent in bed, increased ambulation, healthier attitude and a more varied lifestyle.
The present invention also includes within its scope a method which uses a modified neurotoxin. By a modified neurotoxin it is meant a neurotoxin which has had one or more of its amino acids deleted, modified or replaced (as compared to the native neurotoxin) and includes recombinant technology made neurotoxins as well as derivatives and fragments of a recombinant produced neurotoxin.